Bladder cancer is the fourth most common cancer occurring in the United States, with each year bringing more than 63,210 new cases and 13,180 related deaths. Notably, the incidence of bladder cancer is three times higher in men than women. Estrogen receptors are known to mediate the intracellular actions of estrogens. Two receptor subtypes, estrogen receptor-a (ERa) and ER[unreadable] mediate the nuclear/genomic responses to estrogens and antiestrogens, and they exhibit both separate and overlapping tissue distributions and functions. Expression of ERa and ER[unreadable] have been reported in the urothelium and detrusor muscle of the human bladder, and studies in rats and mice indicate that ER[unreadable] is the predominant form of ER expressed in the bladder epithelium and smooth muscle. Experiments employing ligand binding analyses indicate that ERs are present in transitional cell carcinoma of bladder in humans, and immunological approaches demonstrate ERa expression in 12%-18% of tested bladder cancers. This, however, did not correlate with the prognosis of bladder cancer patients. We have generated data indicating that: 1) ER[unreadable] is expressed in the majority of human bladder transitional cell cancers across a broad spectrum of stage and grade, while ERa is expressed in <5% of tumors;2) ER[unreadable] is expressed in multiple bladder cancer cell lines tested;3) the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, inhibit growth of bladder cancer cell lines in vitro and 4) raloxifene and 4- hydroxytamoxifen reduce the size of bladder cancer xenografts grown in female nude mice. Based on these findings we propose the following hypothesis. SERM effects on bladder cancer cell lines are mediated mainly by ER[unreadable] which is the predominate isoform of the ER expressed in human bladder cancer. SERM treatment of ER[unreadable]-positive bladder cells will inhibit their growth, and therefore will be an effective chemoprevention strategy for bladder cancer. This hypothesis will be tested in the following two specific aims: 1) To investigate the role of estrogen receptor and the ability of estrogen receptor ligands to regulate bladder cancer cell growth, and 2) To study the in vivo anti-tumor effect of selective estrogen receptor modulators in an orthotopic model of human bladder cancer.